Impairments in autonomic function are a major complication of diabetes. The autonomic nervous system involves complex interactions between central neurons and peripheral ganglia. In particular, hypothalamic and brainstem neurons sensitive to glucose and nutritional status play a critical role in regulating the autonomic nervous system. Glucose-sensitive hypothalamic neurons appear to sense glucose through a beta cell-like mechanism. A subset of hypothalamic and brainstem neurons, like beta cells and peripheral neurons but in contrast to other central neurons, are highly sensitive to deleterious effects of and glucose derivatives. Thus some diabetes-induced impairments in autonomic activity may be due to diabetes-induced damage to these glucose-sensitive hypothalamic and brainstem neurons. The proposed studies will characterize effects of diabetes on hypothalamic and brainstem neurons, including effects of diabetes on (i) regulation of key gene products (POMC and CART) thought to be produced by glucose-sensitive neurons; (ii) the ability of these neurons to sense glucose and nutritional status; (iii) structural impairments and possible loss of these neurons. In addition, the proposed studies will assess the correlation between hypothalamic and brainstem impairments and impairments in autonomic ganglia, the vagus nerve, and sympathetic function (regulation of temperature, heart rate, and counterregulatory responses to hypoglycemia). Finally, the proposed studies will assess the role of non-enzymatic glycation in diabetes-induced impairments observed in Studies I and II. Since diabetic neuropathy is thought to entail reversible, presumably metabolic, impairments, and irreversible, presumably structural, impairments, the present study will distinguish between reversible and irreversible impairments by comparing effects of uncorrected diabetes, diabetes corrected with intensive insulin therapy, and diabetes corrected with islet transplants. The present study should clarify the mechanisms and significance of glucose-sensitive hypothalamic and brainstem neurons in autonomic diabetic neuropathy.